1. Field of the Invention
The present invention relates to amorphous solid dispersions of 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a pharmacological agent possessing a high affinity for the peripheral-type benzodiazepine receptors.
This invention also relates to processes for the preparation of these amorphous solid dispersions, to pharmaceutical compositions including such dispersions, and to methods of use thereof for the prevention and treatment of diseases related to peripheral-type benzodiazepine receptors.
2. Description of the Art
7-Chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, which has the structure of Formula (I):
possesses a high affinity for the peripheral-type benzodiazepine receptors. The preparation, physical properties and beneficial pharmacological properties of 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide are described in, for example, U.S. Pat. No. 6,262,045 and, in particular, U.S. Pat. No. 6,395,729, both of which are incorporated by reference in their entirety
The limited solubility of crystalline 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, prepared according to Example 1 of U.S. Pat. No. 6,395,729, in both aqueous solutions and non-aqueous formulation solvents presents difficulties in the administration and storage of formulations containing this compound. Preliminary studies carried out with conventional formulations using this crystalline solid (such as formulations prepared by wet granulation or dry blend processes using standard excipients well known to those of skill in the art) have led to limited absorption of the drug.
Attempts to improve the solubility of the pure drug substance, such as by preparing and utilizing amorphous forms of 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, resulted in drug substance with limited physical stability. For example, such drug substance crystallized over time.
It has now been found that certain polymers are useful for preparing dispersions of solid amorphous 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide having significant solubility improvements over conventional formulations and also possessing significant physical stability improvements over amorphous drug substance alone. Solid amorphous dispersions of poorly soluble drugs in polymers are known generally to improve the solubility of drug products. However, such dispersions are generally unstable over time. Amorphous dispersions of drugs in polymers tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the bioavailability and solubility of crystalline drug material compared to amorphous drug material. One skilled in the art cannot predict which polymers, if any, would be useful for preparing stable amorphous dispersions for a particular drug product. The present invention, however, provides such stable amorphous dispersions with improved solubility.